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Ref Type Journal Article
PMID (28878026)
Authors Le Moigne R, Aftab BT, Djakovic S, Dhimolea E, Valle E, Murnane M, King EM, Soriano F, Menon MK, Wu ZY, Wong ST, Lee GJ, Yao B, Wiita AP, Lam C, Rice J, Wang J, Chesi M, Bergsagel PL, Kraus M, Driessen C, Kiss von Soly S, Yakes FM, Wustrow D, Shawver L, Zhou HJ, Martin TG, Wolf JL, Mitsiades CS, Anderson DJ, Rolfe M
Title The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma.
Journal Molecular cancer therapeutics
Vol 16
Issue 11
Date 2017 11
URL
Abstract Text Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375-86. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CB-5083 CB-5083 1 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
CB-5083 CB-5083 binds to and inhibits valosin-containing protein (VCP, p97) to activate the unfolded protein response, resulting in ER stress, apoptosis, and decreased tumor cell proliferation (PMID: 28878026, PMID: 29314493, PMID: 30606672, PMID: 30591537).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown multiple myeloma not applicable CB-5083 Preclinical - Cell line xenograft Actionable In a preclinical study, CB-5083 treatment of multiple myeloma cell lines and xenografts resulted in cell death and decreased tumor growth, respectively (PMID: 28878026). 28878026